Project Summary A significant fraction of epilepsy patients cannot be effectively treated by current medications. For this reason, new drug targets that can modulate seizure vulnerability are needed. G protein-coupled receptors (GPCRs) are outstanding drugs targets, and thus GPCRs that can influence seizure vulnerability are of special interest to study as potential new drug targets in the treatment of epilepsy. The GPCR known as GPR12 has been linked in genetic studies to epilepsy in humans. Moreover, recent data from our lab has shown that GPR12 forms a complex with the amyloid precursor protein (APP) and exerts striking control over APP expression in cultured cells. These two observations are potentially linked, as APP is known to strongly influence seizure vulnerability in vivo. We hypothesize that GPR12 regulates APP processing via physical association and/or receptor signaling, with this regulation contributing to GPR12 modulation of seizure vulnerability. These ideas will be tested in two aims: i) we will dissect the interaction between GPR12 and APP and determine how GPR12 controls APP expression, and ii) we will examine GPR12-mediated regulation of APP in vivo and also assess GPR12 modulation of seizure vulnerability in a mouse model. If deletion of GPR12 is found to result in both perturbed APP levels in vivo and altered seizure vulnerability, these findings would set the stage for future studies focused on determining how these two observations might be related. Moreover, such findings would also pave the way for the eventual targeting of GPR12 by drug-like small molecules to develop novel therapeutics for the treatment of epilepsy and other disorders. !